Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis

AbstractThe ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure –response–outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log10 CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49% lower drug exposure. To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standardCryptococcus therapy of amphotericin B (0.7 –1.0 mg/kg per day) and fluconazole (800 mg/day) without sertraline. Adjunctive sertraline significantly increased CSF fungal clearance rate compared to COAT trial and sertraline effect was dose-independent with no covariate found to affect fungal clearance including ART. Study findings suggest sertraline response could be mediated by different mechanisms than directly inhibiting the initiation of protein translation as previously suggested; this is supported by the prediction of unbound ser...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research